Abstract:

An adapter for achieving intradermal dosed delivery of a liquid by use of
a dosed drug delivery device including a reservoir having a pierceable
septum, the adapter having a connector including an attachment
configuration for attachment to the dosed drug delivery device and a
hollow needle deployed for piercing the septum. A liquid delivery
interface, linked to the connector, includes a straight skin contact edge
and one or more hollow microneedle adjacent thereto. The microneedle
projects away from the skin contact edge. A flow path arrangement
interconnects the needle and the at least one hollow microneedle.

Claims:

1. An adapter for achieving intradermal dosed delivery of a liquid by use
of a dosed drug delivery device, the dosed drug delivery device including
a reservoir having a pierceable septum, the adapter comprising:(a) a
connector including an attachment configuration for attachment to the
dosed drug delivery device and a hollow needle deployed for piercing the
septum;(b) a liquid delivery interface mechanically linked to said
connector, said liquid delivery interface including a substantially
straight skin contact edge and a linear array of hollow microneedles
deployed substantially adjacent to, and arrayed substantially parallel
to, said skin contact edge, said microneedles projecting away from said
skin contact edge; and(c) a flow path arrangement interconnecting said
needle and said array of hollow microneedles.

2. The adapter of claim 1, wherein each of said microneedles has a height,
and wherein a distance between said skin contact edge and each of said
microneedles is no greater than said height of said microneedles.

3. The adapter of claim 1, wherein said substantially straight skin
contact edge is formed as an edge of a block of material, said block of
material being integrally formed with at least part of said attachment
configuration.

4. The adapter of claim 1, wherein an extensional direction of said hollow
needle of said connector defines a primary flow axis, and wherein each of
said hollow microneedles includes a flow channel defining an injection
direction, said injection direction being inclined relative to said
primary flow axis by an angle of at least 20 degrees.

5. The adapter of claim 4, wherein said injection direction is inclined
relative to said primary flow axis by an angle of between 30 degrees and
150 degrees.

6. The adapter of claim 4, wherein said injection direction is inclined
relative to said primary flow axis by an angle of about 90 degrees.

7. The adapter of claim 1, wherein said hollow microneedles are integrally
formed with a substrate.

8. The adapter of claim 7, wherein said substrate has a substantially
planar surface, and wherein each of said microneedles is formed by at
least one wall standing substantially upright from said substantially
planar surface and an inclined surface intersecting with said at least
one wall.

9. The adapter of claim 8, wherein each of said microneedles has a flow
channel passing through said substrate and intersecting with said
inclined surface.

10. The adapter of claim 7, wherein said microneedles are formed from
silicon.

11. A combination of the adapter of claim 1 with a dosed drug delivery
device, the combination further including a dosed drug delivery device
having a liquid reservoir including a pierceable septum, the adapter
being connected to said dosed drug delivery device so that said hollow
needle pierces said septum thereby bringing said microneedles into flow
connection with contents of said reservoir.

12. The combination of claim 11, wherein said reservoir contains a
quantity of insulin.

13. The combination of claim 11, wherein said reservoir contains a
quantity of a fertility hormone.

14. The combination of claim 11, wherein said reservoir contains a
quantity of a growth hormone.

15. The combination of claim 11, wherein said reservoir contains a
quantity of a vaccine.

16. An adapter for achieving intradermal dosed delivery of a liquid by use
of a dosed drug delivery device, the dosed drug delivery device including
a reservoir having a pierceable septum, the adapter comprising:(a) a
connector including an attachment configuration for attachment to the
dosed drug delivery device and a hollow needle deployed for piercing the
septum;(b) a liquid delivery interface mechanically linked to said
connector, said liquid delivery interface including a substantially
straight skin contact edge and at least one hollow microneedle deployed
substantially adjacent to said skin contact edge, said at least one
microneedle projecting away from said skin contact edge; and(c) a flow
path arrangement interconnecting said needle and said at least one hollow
microneedle.

17. The adapter of claim 16, wherein said at least one hollow microneedle
is implemented as a plurality of hollow microneedles deployed in a
substantially linear array substantially parallel to said skin contact
edge.

Description:

FIELD AND BACKGROUND OF THE INVENTION

[0001]The present invention relates to drug deliver devices and, in
particular, it concerns a microneedle adapter for use with dosed drug
delivery devices.

[0002]Dosed drug delivery devices, often referred to as "pen injectors,"
are commonly used by diabetics for routine injection of insulin. Similar
devices are also used for the delivery of hormones. Dosed drug delivery
devices are a preferred means of delivery wherever the volume of drug
delivered needs to be variable but accurate, small and frequently
administered. Use of the term "pen injector" probably stems from the
elongated pen-like form of many of the commercially available devices.
However, unless otherwise specified, the term "pen injector" will be used
herein interchangeably with the term "dosed drug delivery device" to
refer generically to any and all free-standing portable device containing
a plurality of doses of a therapeutic liquid which can be operated by a
patient for self-injection to deliver metered doses of the liquid to the
patient's body on a plurality of occasions. There are various kinds of
pen injectors which may be variously classified according to different
structural or functional features, such as: devices employing replaceable
cartridges and devices which are disposed of when the contents are
finished; devices with fixed dosage units or with various dialing and
dosing features; devices with different flow activation mechanisms,
ergonomics and design, reservoir systems and volume requirements etc.

[0003]Pen injectors are used with dedicated replaceable needle assemblies,
referred to herein for convenience as "pen needles". Commercially
available pen needles known to the inventors all target the subcutaneous
(SC) fatty layer and make use of tubular metal components (hypodermic
stainless steel needles). Commercially available pen needles typically
have lengths ranging from 1 mm to 25 mm.

[0004]Pen needles are configured to satisfy several requirements unique to
pen injectors. On one side, they feature a connector for reversibly
connecting to a liquid reservoir within the pen injector. The connector
typically includes a hollow needle deployed for piercing a septum
(resilient self-sealing membrane) integrated with the liquid cartridge,
and an attachment configuration such as a threaded collar for attachment
to the pen injector. On the other side, the pen needle features the
skin-penetrating needle. The septum-piercing needle and the
skin-penetrating needle are typically implemented as opposite ends of a
single double-ended needle. The two ends typically have different point
shapes, with the rear end configured to avoid coring of a hole in the
septum and the front end shaped to minimize pain on penetration through
the skin. This renders the double ended needle complex to manufacture. On
the other hand, since a single continuous needle is used, there is
typically no requirement of sealing between the needle and the
surrounding connector body, often allowing the structure to be assembled
without the sealing glue required for other hypodermic applications, and
the "dead volume" of the needle is very small. For all of the above
reasons, design considerations for pen needles are significantly
different from those of other hypodermic needles, and such needles have
attained a distinct status in the art, often being produced by specialist
companies which deal exclusively with pen needles and other pen injector
related accessories.

[0005]Miniature needles used for pen injectors typically project a minimum
of 1 millimeter. In the case of a miniature needle of conventional
hypodermic type (i.e., a metal tube formed with a beveled end), the bevel
of the needle tip itself typically has a length of at least 0.8 mm,
making it impossible to achieve sealed fluid delivery to penetration
depths less than 1 mm.

[0006]In some published documents, it has been proposed to use
"microneedles" as a delivery interface for pen injectors. For the purpose
of the present description and claims, the term "microneedle" in its
broadest sense is used to refer to a projecting structure with a
projecting length of less than 1 millimeter. Examples of such documents
include US patent application publication nos. US 2003/0050602 to Pettis
and US 2003/0181863 to Ackley et al. Theoretically, application of
microneedles to pen injectors promises various advantages attributed to
intradermal delivery including, but not limited to, altered kinetics
(depending on the formulation and the exact injection site, either
accelerated absorption, such as may be beneficial for insulin delivery or
delayed absorption, for example if a slow release formulation is used),
improved response (for example intradermal delivery of vaccines may
enhance immune response, allow for smaller doses, potentially lesser
booster shots, better vaccination, etc), reduced trauma (since
microneedles are smaller than conventional hypodermic needles), and
minimally painful or painless injections. The last feature, in
particular, is considered highly significant, possibly increasing patient
compliance, improving quality of life, improving disease control and
reducing expenses on treatment of disease complications. This is
particularly relevant in the case of insulin injections for treatment of
diabetes due to the direct relation between long term control of blood
glucose levels and the prevalence of long term complications.

[0007]In practice, implementations of microneedles for pen injectors are
not straightforward due to a number of practical problems. A first major
problem of many microneedle designs relates to mechanical weakness of the
microneedles which tend to fracture on contact with the skin,
particularly when exposed to shear forces due to lateral movement. A
further problem is that the highly elastic skin barrier tends to deform
around the microneedles without the microneedles penetrating through the
stratum corneum (SC). An additional problem is that of leakage around the
microneedles' point of insertion and/or ejection of the needles by
back-pressure generated during injection. Many designs are also prone to
blockage of the bores of hollow microneedles due to punching-out of a
plug of tissue during insertion through the skin.

[0008]Solutions to the aforementioned problems have been suggested in the
context of applications such as infusion sets and syringes. Particularly,
reference is made to a particularly advantageous robust microneedle
structure as taught by U.S. Pat. No. 6,533,949, and to various
microneedle insertion techniques as taught by PCT Patent Application
Publication Nos. WO 03/074102 A2 and WO 2005/049107 A2, and in US Patent
Application Publication No. US 2005/0209566 A1, these four publications
mentioned in this paragraph all being hereby incorporated by reference in
their entirety. However, these solutions have not previously been adapted
to address the particular requirements of pen injectors. Furthermore,
given the unique design considerations for pen needles, and the distinct
status of pen needles as established in the art, such adaptations are not
readily apparent to a person having ordinary skill in the art.

[0009]There is therefore a need for an adapter for achieving intradermal
dosed delivery of a liquid by use of a dosed drug delivery device.

SUMMARY OF THE INVENTION

[0010]The present invention is an adapter for achieving intradermal dosed
delivery of a liquid by use of a dosed drug delivery device.

[0011]According to the teachings of the present invention there is
provided, an adapter for achieving intradermal dosed delivery of a liquid
by use of a dosed drug delivery device, the dosed drug delivery device
including a reservoir having a pierceable septum, the adapter comprising:
(a) a connector including an attachment configuration for attachment to
the dosed drug delivery device and a hollow needle deployed for piercing
the septum; (b) a liquid delivery interface mechanically linked to the
connector, the liquid delivery interface including a substantially
straight skin contact edge and a linear array of hollow microneedles
deployed substantially adjacent to, and arrayed substantially parallel
to, the skin contact edge, the microneedles projecting away from the skin
contact edge; and (c) a flow path arrangement interconnecting the needle
and the array of hollow microneedles.

[0012]According to a further feature of the present invention, each of the
microneedles has a height, and wherein a distance between the skin
contact edge and each of the microneedles is no greater than the height
of the microneedles.

[0013]According to a further feature of the present invention, the
substantially straight skin contact edge is formed as an edge of a block
of material, the block of material being integrally formed with at least
part of the attachment configuration.

[0014]According to a further feature of the present invention, an
extensional direction of the hollow needle of the connector defines a
primary flow axis, and wherein each of the hollow microneedles includes a
flow channel defining an injection direction, the injection direction
being inclined relative to the primary flow axis by an angle of at least
20 degrees.

[0015]According to a further feature of the present invention, the
injection direction is inclined relative to the primary flow axis by an
angle of between 30 degrees and 150 degrees.

[0016]According to a further feature of the present invention, the
injection direction is inclined relative to the primary flow axis by an
angle of about 90 degrees.

[0017]According to a further feature of the present invention, the hollow
microneedles are integrally formed with a substrate.

[0018]According to a further feature of the present invention, the
substrate has a substantially planar surface, and wherein each of the
microneedles is formed by at least one wall standing substantially
upright from the substantially planar surface and an inclined surface
intersecting with the at least one wall.

[0019]According to a further feature of the present invention, each of the
microneedles has a flow channel passing through the substrate and
intersecting with the inclined surface.

[0020]According to a further feature of the present invention, the
microneedles are formed from silicon.

[0021]There is also provided according to the teachings of the present
invention, a combination of the aforementioned adapter with a dosed drug
delivery device, the combination further including a dosed drug delivery
device having a liquid reservoir including a pierceable septum, the
adapter being connected to the dosed drug delivery device so that the
hollow needle pierces the septum thereby bringing the microneedles into
flow connection with contents of the reservoir.

[0022]According to a further feature of the present invention, the
reservoir contains a quantity of insulin. Alternatively, the reservoir
contains a quantity of a fertility hormone. In a further alternative, the
reservoir contains a quantity of a growth hormone. In yet a further
alternative, the reservoir contains a quantity of a vaccine.

[0023]There is also provided according to the teachings of the present
invention, an adapter for achieving intradermal dosed delivery of a
liquid by use of a dosed drug delivery device, the dosed drug delivery
device including a reservoir having a pierceable septum, the adapter
comprising: (a) a connector including an attachment configuration for
attachment to the dosed drug delivery device and a hollow needle deployed
for piercing the septum; (b) a liquid delivery interface mechanically
linked to the connector, the liquid delivery interface including a
substantially straight skin contact edge and at least one hollow
microneedle deployed substantially adjacent to the skin contact edge, the
at least one microneedle projecting away from the skin contact edge; and
(c) a flow path arrangement interconnecting the needle and the at least
one hollow microneedle.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]The invention is herein described, by way of example only, with
reference to the accompanying drawings, wherein:

[0025]FIG. 1 is an isometric view of a preferred form of a linear array of
microneedles for use in the adapters of the present invention;

[0026]FIG. 2A is a exploded isometric view of a first embodiment of an
adapter, constructed and operative according to the teachings of the
present invention, for use with a dosed drug delivery device to achieve
intradermal dosed delivery of a liquid;

[0027]FIG. 2B is a isometric partially-cut-away view of the adapter of
FIG. 2A as assembled prior to use;

[0028]FIG. 2c is a cross-sectional view taken through the adapter of FIG.
2B after removal of protective covers;

[0029]FIG. 3 is a cross-sectional view similar to FIG. 2c taken through a
second embodiment of an adapter, constructed and operative according to
the teachings of the present invention, for use with a dosed drug
delivery device to achieve intradermal dosed delivery of a liquid;

[0030]FIG. 4A is a side view of the adapter of FIG. 2B assembled on a pen
injector ready for use;

[0031]FIG. 4B is an enlarged view of the region of FIG. 4A including the
adapter;

[0032]FIG. 5A is a side view of the adapter of FIG. 3 assembled on a pen
injector ready for use;

[0033]FIG. 5B is an enlarged view of the region of FIG. 5A including the
adapter;

[0034]FIG. 6A is a view similar to FIG. 4B after interfacing of the
adapter with the skin of a user;

[0035]FIG. 6B is a view similar to FIG. 6A after injection of a dose of
the liquid;

[0036]FIG. 7A is a view similar to FIG. 5B after interfacing of the
adapter with the skin of a user; and

[0037]FIG. 7B is a view similar to FIG. 7A after injection of a dose of
the liquid.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038]The present invention is an adapter for use with a dosed drug
delivery device to achieve intradermal dosed delivery of a liquid.

[0039]The principles and operation of adapters according to the present
invention may be better understood with reference to the drawings and the
accompanying description.

[0040]By way of introduction, the present invention relates to an
adaptation of a microneedle drug delivery interface and corresponding
technique described in US Patent Application Publication No. US
2005/0209566 A1 to render it suitable for use as a disposable drug
delivery interface for pen injectors. The adapter most preferably employs
microneedles produced by MEMS techniques from a single-crystal block of
material such as silicon according to the teachings of U.S. Pat. No.
6,533,949. Alternatively, various other forms of microneedles and/or
other materials may be used, such as are taught in U.S. Pat. No.
6,503,231 to Prausnitz et al. These documents are hereby incorporated by
reference herein and provide helpful background to the present invention.

[0041]Referring now to the drawings, FIG. 1 shows a particularly preferred
implementation of a linear array 10 of microneedles for use in the
adapter of the present invention. Specifically, linear array 10 includes
a number of hollow microneedles, typically between 1 and 10, more
preferably between 3 and 6, and in the preferred case illustrated here,
4. Each microneedles has a penetrating point 1, a liquid flow channel 2
and preferably also a cutting edge 3. The microneedles are preferably
integrally formed with a substrate 5, having a substantially planar
surface. In the preferred implementation shown here, each microneedle is
formed by a set of one or more walls 6 standing substantially upright
from the substantially planar surface of substrate 5, and an inclined
surface 7 intersecting with walls 6. Flow channel 2 is preferably formed
as a bore passing through substrate 5 and intersecting with inclined
surface 7. The linear microneedle array 10 is preferably formed using a
combination of dry etching and wet etching processes from a single
crystal of material, most preferably silicon, by techniques such as those
described in detail in the aforementioned U.S. Pat. No. 6,533,949.
Preferred dimensions for the microneedles for this application are a
total height in the range of 250 to 650 microns, and most preferably
450±30 micron. The flow channel 2 may be round or of other
cross-sectional shape, and preferably has a minimum internal diameter of
about 45±10 microns if round, and an equivalent minimum
cross-sectional area if otherwise shaped.

[0042]Turning now to FIGS. 2A-2C, these illustrate a first preferred
embodiment of an adapter, generally designated 50, constructed and
operative according to the teachings of the present invention, for
achieving intradermal dosed delivery of a liquid by use of a dosed drug
delivery device. Generally speaking, adapter 50 includes a connector
including an attachment configuration 22 for attachment to a dosed drug
delivery device, and a hollow needle 25 deployed for piercing a septum of
a reservoir (typically, a cartridge such as a shell vial with moveable
plug) of the dosed drug delivery device. Adapter 50 also features a
liquid delivery interface 24, mechanically linked to the connector,
including a substantially straight skin contact edge 26 and linear array
10 of hollow microneedles deployed substantially adjacent to, and arrayed
substantially parallel to, skin contact edge 26. The microneedles
preferably projecting away from the skin contact edge 26. A flow path
arrangement 28 interconnects needle 25 with the flow channels of the
microneedles in linear array 10.

[0043]Prior to use, adapter 50 is preferably protected by a front cover
30, as shown in FIGS. 2A and 2B, which protects the microneedles from
accidental mechanical damage. Front cover 30 preferably also seals
against a peel-off backing sheet 35 which prevents accidental contact
with needle 25 and maintains sterility, together forming a pre-sealed
sterile packaging for adapter 50. The device can be sterilized using
common methods such as Gamma irradiation or exposure to Ethylene Oxide.

[0044]The mode of use of adapter 50 will be understood with reference to
FIGS. 4A, 4B, 6A and 6B. First, after removal of backing sheet 35,
attachment configuration 22 is attached instead of a pen needle to a
conventional pen injector 100, as shown in FIG. 4A and enlarged in FIG.
4B. As adapter 50 is attached to the pen injector, needle 25 (not visible
in this view) pierces the septum of the liquid vial or cartridge within
the pen injector, thereby forming a flow connection to the microneedles.
Then, as shown in FIG. 6A, the assembled device is brought into contact
with the user's skin and pushed gently with a vector of motion having a
non-zero component parallel to the initial surface of the skin (to the
right as shown) so as to achieve penetration with the microneedles
projecting primarily sideways, parallel to the initial surface of the
skin. This form of insertion achieves numerous advantages over
conventional perpendicular insertion, as detailed in the aforementioned
US Patent Application Publication No. US 2005/0209566 A1. The pen
injector is then actuated in the normal manner to achieve injection of
the desired dose of the contained liquid, as illustrated schematically in
FIG. 6B.

[0045]At this stage, it will already be apparent that the adapter of the
present invention provides profound advantages over the prior art.
Specifically, all pen injector art known to the inventors maintains the
conventional approach of perpendicular insertion of the needle(s) into
the skin, thereby suffering from the aforementioned limitations of
penetration depths in excess of 1 millimeter for conventional needles, or
problems of incomplete penetration and ejection by back pressure for
microneedles. In contrast, by providing the unique geometry of the
present invention in which an array of microneedles are adjacent to a
skin contact edge, the present invention facilitates insertion of
microneedles so that the microneedle flow channels are directed sideways,
i.e., at an angle in the range of ±30° from the initial plane
of the skin surface, into tissue not squashed under the device. As a
result, the adapter of the present invention allows a pen injector to be
used to achieve shallower intradermal liquid delivery than is possible
using conventional devices, and is believed to encounter reduced flow
impedance and achieve better intradermal distribution than would
otherwise be achieved. These and other advantages of the present
invention will be better understood with reference to the following
description.

[0046]Turning now to the features of the present invention in more detail,
skin contact edge 26 is preferably formed as an edge of a block of
material which supports the microneedle array 10. Most preferably, this
block is integrally formed with at least part of the attachment
configuration. Thus, in the example of FIGS. 2A-2C, adapter 50 is most
preferably formed from a combination of only three elements: microneedle
array 10, needle 25, and a unitary body 20 formed from molded polymer
material which provides both the attachment configuration (in this case,
a threaded collar) and support for microneedle array 10. Most preferably,
body 20 is formed from molded polycarbonate. This three-element
implementation minimizes production costs, rendering the adapter suitable
for disposable use as a pen needle substitute.

[0047]Body 20 also preferably defines any flow paths 28 required to
interconnect needle 25 with the flow channels of the microneedles. In the
preferred implementation shown, this includes a transverse open channel
formed under the point of attachment of microneedles array 10 so that,
when the substrate is attached by use of adhesive, welding or other known
methods, the channel together with the rear surface of the substrate
forms a closed channel for distributing liquid from needle 25 to all of
the microneedles. The positioning of this channel is chosen to intersect
a central axis of the adapter 50 along which needle 25 is aligned,
thereby simplifying manufacture of body 20, as will be clear to one
familiar with plastic injection molding technology.

[0048]The form of body 20 is chosen to facilitate bringing the
microneedles into contact with the skin in the correct orientation. In
the preferred example shown here, body 20 is formed with a forward
projecting portion which is roughly rectangular in cross-section, having
a major dimension parallel to the extensional direction of microneedle
array 10 and a minor dimension perpendicular thereto. The microneedles
are preferably deployed with the inclined surface having flow channel 2
facing downwards, i.e., inwards towards the depth of the tissue.

[0049]In order to optimize the sideways insertion geometry, the
microneedles are preferably close to edge 26. Preferably, a distance
between skin contact edge 26 and each of the microneedles, defined as the
distance between edge 26 and the closest part of the base of the
microneedles, is no greater than the height of the microneedles
themselves as measured perpendicular to the surface of the substrate.
Most preferably, the microneedles are juxtaposed with their base starting
substantially at edge 26. Parenthetically, it should be noted that edge
26 itself may be provided by either the edge of the substrate of
microneedle array 10 or by an edge of body 20 adjacent to the array 10.

[0050]It will be noted that adapter 50 causes a significant deflection of
the flow direction between the axial direction of the dosed drug delivery
device (corresponding to the direction of needle 25) and the injection
direction as defined by the flow channels of the microneedles. This
deflection is preferably at least about 20 degrees and, more preferably,
between about 30 and about 150 degrees. In the case shown here, the
deflection is roughly 40 degrees. Nevertheless, in order to achieve an
injection direction near parallel to the initial plane of the skin, this
embodiment requires deployment of the pen injector at an inclination as
shown in FIGS. 4A, 4B, 6A and 6B.

[0051]Parenthetically, although the device is illustrated here in a
preferred embodiment in which a linear array of microneedles is used, it
should be noted that a minimal embodiment in which a single microneedle
is used in proximity to skin contact edge 26 also falls within the broad
scope of the present invention.

[0052]FIGS. 3, 5A, 5B, 7A and 7B illustrate an alternative embodiment of
an adapter, generally designated 55, which provides a larger deflection
of the flow direction, namely, about 90 degrees. This orientation
achieves sideways injection while allowing the device to be held
generally orthogonally to the initial skin surface, in a manner more
similar to the orientation of a pen injector used with a conventional pen
needle. Initial insertion of the microneedles into the skin surface is
preferably performed at a slight angle, as illustrated in FIGS. 5A and
5B, and typically requires a slight turning motion, applying an
anticlockwise turning moment in the orientation as illustrated in FIG.
7A.

[0053]In other respects, the structural features and function of adapter
55 will be understood by analogy to the corresponding features and
function of adapter 50 described above, with like elements being labeled
similarly.

[0054]It will be appreciated that the present invention may be used to
advantage in a large number of drug delivery applications, including both
applications for which pen injectors are conventionally used and new
applications for which the shallow intradermal delivery achieved by the
present invention may be advantageous. Examples of applications include,
but are not limited to, administering: insulin, fertility hormones,
growth hormone and vaccines. Other applications include, but are not
limited to, the substances and modes of treatment mentioned in US Patent
Application Publication No. 2005/0163711 A1, which is hereby incorporated
by reference herein.

[0055]It will be appreciated that the above descriptions are intended only
to serve as examples, and that many other embodiments are possible within
the scope of the present invention as defined in the appended claims.